The subject invention relates to the art of delivering bioaffecting agents, such as drugs, to bio-systems, and, in particular, for rendering agents which are substantially non-dissoluble in an aqueous environment available for interaction with a host bio-system, such as a human or other animal.
Bio-systems, such as humans, plants, insects, fish, birds, and mammals, are primarily aqueous systems. In order to effectively deliver a bioaffecting agent to such bio-systems, it is necessary to make the agent available for interaction with physiological activity in the bio-system. This is referred to herein as “bio-availability”. In the case of bioaffecting agents that are non-dissoluble in an aqueous environment, as well as in the case of those that are only poorly water-soluble, effective administration of the bioaffecting agent can be difficult due to inadequate bio-availability of the agent and consequent low pharmacological activity. These solubility problems affect many parameters of delivery, such as the method of administration, the rate of administration, the concentration of administration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing the ratio of surface area/mass of the solid, for example, by decreasing the particle size. Consequently, methods of making finely divided drugs have been studied, and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and thereby influence drug absorption. However, in conventional dry milling, as discussed by Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, “Milling”, p. 45 (1986), the limit of fineness is reached in the region of about 100 μm (=100,000 nm), where the milled material begins to cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 μm (=10,000 nm). There tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 μm to 50 μm (=1,000 nm to 50,000 nm).
Other techniques for preparing pharmaceutical compositions with enhanced aqueous solubility properties include loading drugs into liposomes or polymers, such as, for example, during emulsion polymerization. However, such techniques have inherent problems and limitations. For example, a lipid-soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator (which can be toxic) at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular weight substance using a wet grinding machine. However, the '602 patent teaches that, as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 μm (500 nm) to less than 5 μm (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance, and results in the formation of non-crystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly, precipitation methods are usually impractical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 describes a method for providing drug particles having an effective average particle size of less than about 400 nm. The method includes wet milling the drug in the presence of a grinding medium in conjunction with a surface modifier. As in previous methods, the '684 protocol requires grinding or milling to achieve size reduction. The method further requires the use of an additive in the form of a surface modifier.
Moreover, drugs prepared by milling, even wet milling such as that described in the '684 disclosure, are subject to degradation resulting from heat as well as physical and chemical trauma associated with fracture. Grinding also creates “hot spots,” i.e., volumes of localized higher temperatures that can exceed the melting point or degradation of the drug. The process is also lengthy, requiring attrition exposure over several days. This type of process effectively exposes the drug to a long “heat history”, wherein exposure to elevated temperatures has been significant, and the purity and potency of the drug is diminished to a significant extent. Furthermore, particles reduced by milling are often contaminated by, the residue of the grinding operations, especially when ball milling is used and the grinding balls are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by aggregating substantially non-dissoluble active ingredients on the surface of soluble substrates, such as water-soluble beads. The active ingredient can be deposited on such substrates by spraying a solution of the active ingredient over a fluidized bed while “flashing off” the solvent used for the active ingredient. This method is highly inefficient in that it requires several hours to deposit a sufficient amount of active ingredient to prepare a useable delivery system. Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e., the solvent required to dissolve the active ingredient. As previously mentioned, the solvent must be flashed off during aggregation. Thus, this system is a long and cumbersome process and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs that have low aqueous solubility require the use of organic solvents for processing in a solution state. This requires the use of expensive recovery systems for solvent handling capability. When general melt processing techniques are used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged heat history.
Particulate carriers have been used in order to achieve controlled, parenteral delivery of therapeutic compounds. Such carriers are designed to maintain the active agent in the delivery system for an extended period of time. Examples of particulate carriers include those derived from polymethyl methacrylate polymers, as well as microparticles derived from poly(lactides) (see, e.g., U.S. Pat. No. 3,773,919), poly(lactide-co-glycolides), known as PLG (see, e.g., U.S. Pat. No. 4,767,628) and polyethylene glycol, known as PEG (see, e.g., U.S. Pat. No. 5,648,095). Polymethyl methacrylate polymers are nondegradable, while PLG particles biodegrade by random nonenzymatic hydrolysis of ester bonds to lactic and glycolic acids, which are excreted along normal metabolic pathways.
For example, U.S. Pat. No. 5,648,095 describes the use of microspheres with encapsulated pharmaceuticals as drug delivery systems for nasal, oral, pulmonary, and oral delivery. Slow-release formulations containing various polypeptide growth factors have also been described. See, for example, International Publication No. WO 94/12158, U.S. Pat. No. 5,134,122 and International Publication No. WO 96/37216.
Fattal et al., Journal of Controlled Release 53:137-143 (1998) describes nanoparticles prepared from polyalkylcyanoacrylates (PACA) having adsorbed oligonucleotides.
U.S. Pat. Nos. 5,814,482 and 6,015,686 disclose Eukaryotic Layered Vector Initiation Systems (ELVIS vectors), particularly those derived and constructed from alphavirus genomes (such as Sindbis virus), for use in stimulating an immune response to an antigen, in methods of inhibiting pathogenic agents, and in delivery of heterologous nucleotide sequences to eukaryotic cells and animals, among others.
While antigen-adsorbed PLG microparticles offer significant advantages over other more toxic systems, adsorption of biologically active agents to the microparticle surface can nonetheless be improved. For example, it is often difficult or impossible to adsorb charged or bulky biologically active agents, such as polynucleotides, large polypeptides, and the like, to the microparticle surface. Thus, there is a continued need for flexible delivery systems for such agents, and particularly for drugs that are highly sensitive and difficult to formulate.
“Controlled release” refers to the release of an agent such as a drug from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. For example, in the treatment of chronic pain, controlled release formulations are often highly preferred over conventional short-acting formulations.
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A controlled release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bioavailability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
As indicated above, the term “bioavailability” is used to describe the degree to which a drug becomes available at the site(s) of action after administration. The degree and timing in which an agent such as a drug becomes available to the target site(s) after administration is determined by many factors, including the dosage form and various properties such as dissolution rate of the drug. It is well known that some drug compositions suffer from poor bioavailability because of poor solubility of the active ingredient itself.
Numerous methods have been developed for enhancing the bioavailability of poorly soluble drugs. Particle size reduction, such as nanoparticulate forms of the agent, is one such method since the dissolution rate of a compound is related to the particle size. Nanoparticulate compositions comprise poorly water-soluble drug or agent particles having an extremely small particle size, i.e., less than one micron. With a decrease in particle size, and a consequent increase in ratio of surface area/mass, a composition tends to be rapidly dissolved and absorbed following administration. For certain formulations, this characteristic can be highly desirable, as described, for example, in U.S. Pat. Nos. 5,145,684; 5,510,118; 5,534,270; and 4,826,689; which are specifically incorporated by reference. However, rapid dissolution is contrary to the goal of controlled release. Known controlled release formulations do not present a solution to this problem.
Prior art teachings of the preparation and use of compositions providing for controlled release of an active compound provide various techniques for extending the release of a drug following administration. However, none of the techniques suggest a successful method of administering a nanoparticulate formulation.
Exemplary controlled release formulations known in the art include specially coated pellets, microparticles, implants, tablets, minitabs, and capsules in which the controlled release of a drug is brought about, for example, through selective breakdown of the coating of the preparation, through release through the coating, through compounding with a special matrix to affect the release of a drug, or through a combination of these techniques. Some controlled release formulations provide for pulsatile release of a single dose of an active compound at predetermined periods after administration.
U.S. Pat. No. 5,110,605 refers to a calcium polycarbophil-alginate controlled release composition. U.S. Pat. No. 5,215,758 refers to a controlled release suppository composition of sodium alginate and calcium salt. U.S. Pat. No. 5,811,388 to refers to a solid alginate-based formulation including alginate, a water-swellable polymer, and a digestible hydrocarbon derivative for providing controlled release of orally administered compounds.
WO 91/13612 refers to the sustained release of pharmaceuticals using compositions in which the drug is complexed with an ion-exchange resin. The specific ion-exchange resin described in this published patent application is AMBERLITE IRP 69®, a sodium polystyrene sulphonate resin.
U.S. Pat. No. 5,811,425 refers to injectable depot forms of controlled release drugs made by forming microencapsule matrices of the drug in biodegradable polymers, liposomes, or microemulsions compatible with body tissues. U.S. Pat. No. 5,811,422 refers to controlled release compositions obtained by coupling a class of drugs to biodegradable polymers, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, etc.
U.S. Pat. No. 5,811,404 refers to the use of liposomes having prolonged circulation half-lives to provide for the sustained release of drug compositions.
Following an administration of a drug in a living system, the active substance is distributed throughout the body as a function of its physicochemical properties and molecular structure. The final amount of drug reaching its target site may only be a small fraction of the administered dose. Accumulation of drug at the non-targeted site may lead to adverse effect and undesirable side reactions. Therefore, targeting of drug to specific body sites is desirable.
One way of modifying the biodistribution of drugs in the body is to entrap them in ultrafine drug carriers. Among these carriers, liposomes, nanoparticles and pharmacosomes have been extensively studied. The use of liposomes as drug targeting agents is found to be limited due mainly to the problems of low entrapment efficiency, drug instability, rapid drug leakage, and poor storage stability. With the aim of overcoming these problems, the production of polymeric nanoparticles has been investigated since the last two decades. Nanoparticles are defined as solid colloidal particles ranging in size from about 10 nm to 1000 nm.
A large number of studies have reported recent advances in drug targeting possibilities and sustained release action with nanoparticles encapsulating drugs. In vivo studies have also been reported with special attention to the reticuloendothelial system (RES). Some in vivo studies concerning nanoparticles administration by oral and ocular routes have also been reported in the literature with respect to the possible improvements of bioavailability. These polymeric nanoparticles should be non antigenic, biocompatible, and biodegradable.
The important characteristics of the particles used for targeting at specific body sites have been found to be influenced mainly by two factors: (i) the size of the nanoparticles and (ii) the surface characteristics of the nanoparticles. Particles smaller than 7 μm, and especially nanoparticles, are not filtered in the lung and their biodistribution is dependent on their interaction with reticuloendothelial system (RES). Biodegradable nanoparticles are mainly taken up by the Kupffer cells in the liver while a small amount of these particles go to macrophages in spleen and bone marrow. Bone marrow uptake and targeting at other sites can be modified drastically by reducing the particle size. Nanoparticles of 200 nm diameter and above have biodistribution dependent on their interaction with RES. The distribution, however, can be reversed if the particle size is made much smaller (for example, below 100 nm) and particle surfaces are made hydrophilic. These small particles in the blood serum do not adsorb serum protein through opsonisation and, as a result, their circulation time in blood is considerably increased. Hydrophobic particles are removed from the circulation very rapidly due to opsonisation. Nanometer-sized particles with a hydrophilic surface remain in blood for a longer period of time so that targeting at specific sites may be facilitated.
It is desirable to provide stable dispersible drug particles in the sub-micrometer size range that can be readily prepared in the absence of size reduction by grinding or milling. Moreover, it would be highly desirable to provide pharmaceutical compositions having enhanced bio-availability. There also remains a need in the art for controlled release nanoparticulate compositions.